Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tirapazamine (TPZ) is a bioreductive drug that exhibits greatly enhanced cytotoxicity in hypoxic tumor cells, which are frequently radiation-resistant and chemoresistant. TPZ exhibits particularly good activity when combined with alkylating agents such as cyclophosphamide (CPA). The present study examines the potential of combining TPZ with CPA in a cytochrome P450-based prodrug activation gene therapy strategy. Recombinant retroviruses were used to transduce 9L gliosarcoma cells with the genes encoding P450 2B6 and NADPH-P450 reductase. Intratumoral coexpression of P450 2B6 with P450 reductase sensitized 9L tumor cells to CPA equally well under normoxic (19.6% O2) and hypoxic (1% O2) conditions. The P450 2B6/P450 reductase combination also sensitized 9L tumor cells to TPZ under both culture conditions. Interestingly, bystander cytotoxic effects were observed for both CPA and TPZ under hypoxia. Furthermore, TPZ exerted a striking growth-inhibitory effect on CPA-treated 9L/2B6/P450 reductase cells under both normoxia and hypoxia, which suggests the utility of this drug combination for P450-based gene therapy. To evaluate this possibility, 9L tumor cells were transduced in culture with P450 2B6 and P450 reductase and grown as solid tumors in severe combined immune deficient mice in vivo. Although these tumors showed little response to TPZ treatment alone, tumor growth was significantly delayed, by up to approximately four doubling times, when TPZ was combined with CPA. Some toxicity from the drug combination was apparent, however, as indicated by body weight profiles. These findings suggest the potential benefit of incorporating TPZ, and perhaps other bioreductive drugs, into a P450/P450 reductase-based gene therapy strategy for cancer treatment.
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PMID:Combination of the bioreductive drug tirapazamine with the chemotherapeutic prodrug cyclophosphamide for P450/P450-reductase-based cancer gene therapy. 1091 48

Bioreductive drugs are a class of hypoxia selective drugs that are designed to eradicate the hypoxic fraction of solid tumors. Their activity depends upon a number of biological and pharmacological factors and we used a mathematical modeling approach to explore the dynamics of tumor growth, infusion, and penetration of the bioreductive drug Tirapazamine (TPZ). An in-silico model is implemented to calculate the tumor mass considering oxygen and glucose as key microenvironmental parameters. The next stage of the model integrated extra cellular matrix (ECM), cell-cell adhesion, and cell movement parameters as growth constraints. The tumor microenvironments strongly influenced tumor morphology and growth rates. Once the growth model was established, a hybrid model was developed to study drug dynamics inside the hypoxic regions of tumors. The model used 10, 50 and 100 \mu {\rm M} as TPZ initial concentrations and determined TPZ pharmacokinetic (PK) (transport) and pharmacodynamics (cytotoxicity) properties inside hypoxic regions of solid tumor. The model results showed that diminished drug transport is a reason for TPZ failure and recommend the optimization of the drug transport properties in the emerging TPZ generations. The modeling approach used in this study is novel and can be a step to explore the behavioral dynamics of TPZ.
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PMID:A hybrid cellular automaton model of solid tumor growth and bioreductive drug transport. 2322 Oct 82